Delivery of anti-cancer drugs using microbubble-assisted ultrasound in digestive oncology: from preclinical to clinical studies

ABSTRACT

Introduction

The combination of microbubbles (MBs) and ultrasound (US) is an emerging method for the noninvasive and targeted enhancement of intratumor chemotherapeutic uptake. This method showed an increased local drug extravasation in tumor tissue while reducing the systemic adverse effects in various tumor models.

Area covered

We focused on preclinical and clinical studies investigating the therapeutic efficacy and safety of this technology for the treatment of colorectal, pancreatic, and liver cancers. We discussed the limitations of the current investigations and future perspectives.

Expert opinion

The therapeutic efficacy and the safety of delivery of standard chemotherapy regimen using MB-assisted US have been mainly demonstrated in subcutaneous models of digestive cancers. Although some clinical trials on pancreatic ductal carcinoma and hepatic metastases from various digestive cancers have shown promising results, successful evaluation of this method in terms of US settings, chemotherapeutic schemes, and MBs-related parameters will need to be addressed in more relevant preclinical models of digestive cancers, in small and large animals before fully and successfully translating this technology for clinic use. Ultimately, a clear evidence of the correlation between the enhanced intratumoral concentrations of therapeutics and the increased therapeutic response of tumors have to be provided in clinical trials.

KEYWORDS:

• Digestive cancer
• drug delivery
• anti-cancer drugs
• ultrasound
• microbubble

Abbreviation list

CRC: Colorectal cancer

CECT: Contrast-enhanced computed tomography

CT: Computed tomography

CTC: Common Toxicity Criteria

DC: Duty cycle

DOC: Docetaxel

DOX: Doxorubicin

ECOG: Eastern cooperative oncology group

FDG: Fluorodeoxyglucose

FOLFIRI: Calcium folinate, 5-fluorouracil, irinotecan

FOLFIRINOX: Calcium folinate, 5-fluorouracil, irinotecan, oxaliplatin

H&E: Hematoxylin and eosin

i.p.: intraperitoneal

i.v.: intravenous

i.t.: intratumoral

MB: Microbubbles

MRI: Magnetic resonance imaging

PC: Pancreatic cancer

PCNA: Proliferating cell nuclear antigen

PDAC: Pancreatic ductal adenocarcinoma

PET: Positron emission tomography

PNP: Peak negative pressure

PRF: Pulse repetition frequency

RECIST: Response evaluation criteria in solid tumors

s.c.: subcutaneous

TUNEL: Terminal deoxynucleotidyl transferase dUTP nick end labeling

US: Ultrasound

Article highlights

• MB-assisted US is an emerging and promising method for non-invasive and targeted delivery of chemotherapeutics.

• MB-assisted US promotes the permeabilization of blood-tumor barriers, thus increasing the extravasation and the i.t. bioavailability of therapeutics; the enhanced i.t. accumulation of therapeutics increases their treatment efficacies, while reducing side effects in healthy tissues.

• Acoustically mediated drug delivery is mainly developed and validated in s.c. animal models of digestive cancers. Further preclinical additional studies have to be performed on orthotopic and metastasis animal models of digestive cancers in small and large animals to confirm the potential therapeutic benefit of this strategy.

• Few Phase I/II clinical trials have reported promising results for the treatment of inoperable pancreatic ductal adenocarcinoma (primary lesions and metastases) and hepatic metastases; and new results are expected on the treatment of hepatic metastases from colorectal and pancreatic cancers.

• Careful evaluation of efficacy and tolerability of therapeutic schemes including the choice of chemotherapy regimen, US settings, choice of MBs is required to facilitate translation of this US technology to the clinic.

• Clinical investigations have to bring a clear evidence of the correlation between the enhanced intratumor concentrations of therapeutics and the increased therapeutic response of tumors to the therapeutics.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the materials. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This work was supported by INCa/DGOS PRTK15-TK/Sonchimio (2017-000159-15), Ligue Contre le Cancer, Cancéropôle Grand-Ouest, Inserm and University of Tours (AB).